The prevalence of HIV-associated neurocognitive disorders (HAND) has increased owing to the widespread use of combined antiretroviral treatment (CART) and resulting longer survival of HIV-infected patients. Among HIV-seropositive patients on CART, most suffer from the milder forms of HAND. Despite the increased prevalence of HAND, we lack good biomarkers for the disease (Price, 2010). Recently, blood sugar metabolism abnormalities have been identified in HIV-infected individuals and associated with HAND. In addition, retrospective data from our own cohort of HIV-seropositive women on CART show that high plasma soluble insulin receptor (sIR) full-length levels are associated with the presence and severity of HAND. Our long-term goal is to identify a biomarker for HAND. The rationale for the current study lies with previous observations by our lab and others that blood sugar metabolism abnormalities are associated with HAND. Our central hypothesis is that these abnormalities contribute to the development and progression of HAND. The objective of the present study is to determine if changes in plasma sIR full-length levels are associated with milder forms of HAND in a cohort of HIV-seropositive women using CART. We propose 3 aims: 1. To determine if sIR ectodomain (1) and full-length (12) subunits are increased in HIV-infection in a cohort of HIV- seropositive women using CART, 2. To determine if high plasma sIR full-length levels are associated with HAND, and 3. To determine if alternative splicing of the insulin receptor mRNA transcript correlates with plasma sIR full-length levels in HIV-seropositive women with HAND. We expect to find an association between plasma sIR full-length and HAND, and increased sIR full-length to be associated with increased alternative splicing of IR mRNA. This study is novel in testing the possibility that plasma sIR full-length could serve as a blood biomarker for presence and severity of HAND. It is significant since sIR full-length could assist in early diagnosis and monitoring treatment responses, as well as in understanding the pathogenic processes of HAND. PUBLIC HEALTH RELEVANCE: We found that plasma soluble insulin receptor levels are associated with the presence and severity of HIV- associated neurocognitive disorders (HAND) in HIV-seropositive women on combined antiretroviral treatment (CART). We propose to further evaluate this association and explore its underlying mechanisms. If our findings are positive, we will have identified a blood biomarker for the early diagnosis and treatment of HAND in HIV- seropositive women on CART.